Obesity is reaching epidemic proportions in the U.S. and poses a serious public health burden due to a wide range of cdmorbidities. Two of the most common complications of obesity are sleep apnea (SA) and type 2 diabetes, and recent evidence suggests that the intermittent hypoxia (IH)and sleep fragmentation (SF) that characterize sleep apnea may independently cause glucose intolerance and insulin resistance and accelerate the process by which obesity leads to diabetes. Potentially both the IH and SF may affect metabolic function, and the major purpose of the current proposal is to delineate the pathways and mechanisms through which IH and SF lead to glucose intolerance and insulin resistance. We propose that impaired signaling of leptin and melanocortin pathways, which normally regulate food intake, metabolism, and insulin sensitivity of peripheral tissues can cause insulin resistance in the presence of IH. Furthermore, we propose that SF can act through different pathways to produce insulin resistance by stimulating the sympathoadrenal axis. Our approach is to examine the effects of validated models of IH and SF in normal and obesity/diabetic prone inbred mice, and to utilize specific transgenic and knockout mice to explore the functional significance of leptin, melanocortin, and adrenergic pathways. We will employ state-of-the-art clinical parameters for measurement of insulin sensitivity (hyperinsulinemic euglycemic clamp), glucose tolerance (intravenous glucose tolerance test), and hepatic glucose output. Specifically, we propose: (1) To determine the magnitude of insulin resistance that occurs in wildtype and leptin-deficient mice exposed to IH and SF, and whether central and peripheral administration of exogenous leptin protects against insulin resistance during IH and SF. (2) To investigate whether endogenous or exogenous blockade of the melanocortin pathway leads to insulin resistance during IH and SF. (3) To examine the role of the role of a-adrenergic receptors and corticosterone increasing insulin resistance, and /?3-adrenergic receptors decreasing insulin resistance in response to IH and SF. The proposed experiments will elucidate causative pathways through which IH and SF lead to insulin resistance in peripheral tissues and identify potential intervention sites for reducing the risk of sleep apnea accelerating the progression of insulin resistance in obese patients.